课题基金 / 基金详情

Virus-targeted therapeutic for EBV-Associated Malignancies

Virus-targeted therapeutic for EBV-Associated Malignancies
EBV 相关恶性肿瘤的病毒靶向治疗
批准号:
9312763
负责人:
SUSAN Park PERRINE
金额:
$51.96万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-09-26 至 2019-06-30

项目摘要

项目成果

SUSAN Park PERRINE的其他基金

相似基金

相关文献

中文摘要
翻译
 描述(申请人提供)爱泼斯坦-巴尔病毒(EBV)与许多人类恶性肿瘤有关,并可能在两种地方性肿瘤:非洲伯基特淋巴瘤(BL)和鼻咽癌(NPC)中起因果作用。克隆性EBV可见于Burkitt淋巴瘤、T/NK淋巴瘤和移植后淋巴增生性疾病(LPD),以及一些T细胞和B细胞淋巴瘤,以及一半的霍奇金淋巴瘤。此外,EBV可能参与其他肿瘤的发展,包括艾滋病相关肉瘤、胃癌和某些乳腺癌。然而,我们已经证明,仅仅是病毒在肿瘤中的存在就为有针对性的治疗策略提供了机会。EBV在这些肿瘤中以休眠或“潜伏”状态持续存在。许多疱疹病毒家族感染的细胞可以被核苷类似的抗病毒前药物杀死,如更昔洛韦,它破坏病毒胸苷激酶(TK)酶。EBV对这些抗病毒药物具有耐药性,因为潜伏感染的肿瘤细胞不表达病毒(TK)酶。我们已经证明,在肿瘤细胞中诱导EBV-TK基因表达的选定药物使肿瘤对标准抗病毒药物易感。这是一种肿瘤靶向治疗,因为只有肿瘤 细胞(含有EBV)被杀死,正常细胞幸免于难。我们已经成功地对EBV相关淋巴系统恶性肿瘤患者进行了这种病毒靶向治疗方法的I/II期研究,这些患者对传统的放射和化疗都是耐药的。我们的靶向治疗在一个治疗周期内取得了26%的完全临床反应(CRS)和40%的良好部分反应(PR)(总的肿瘤缓解率为67%)。这是一个异常高的应答率,不良事件情况良好。这项SBIR建议的总体目标是开发一种更有效、更具选择性和患者更容易获得的病毒靶向治疗方法,用于EBV+恶性肿瘤的测试。在我们的第一阶段,我们已经筛选、验证和选择了一种高度有效的临床阶段的铅诱导剂,这种诱导剂是口服的,具有重要的人体安全性数据,与EBV淋巴瘤的抗病毒药物联合使用。在这个第二阶段的提案中,我们将完成针对这一特定适应症的病毒诱导剂的临床前开发,产生数据以扩大其潜在的治疗应用和价值,并为第二阶段的概念验证临床试验做准备。我们在这项第二阶段建议中的具体目标是:1.优化先导化合物-在动物模型中提炼这种EBV/KSHV靶向治疗方案;将这一治疗方法扩大应用于其他疱疹病毒相关的恶性肿瘤;完成临床前开发;4.)临床试验计划和设置。可衡量的成果和交付成果:i.)优化治疗方案;二.)在与γ疱疹病毒相关的其他恶性肿瘤中验证这种病毒靶向方法;3.)完成先导化合物的临床前开发;iv.)提交第二阶段临床试验的IND。
英文摘要
 DESCRIPTION (provided by applicant) Epstein-Barr virus (EBV) is associated with a number of human malignancies, and likely plays a causal role in two endemic tumors: African Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC). Clonal EBV can be found in Burkitt's lymphomas, T/NK lymphomas, and post-transplant lymphoproliferative disorders (LPD), as well as some T- and B-cell lymphomas, and half of Hodgkin's lymphomas. In addition, EBV may be involved in the development of other neoplasias, including AIDS-related sarcomas, and gastric carcinomas, and certain breast carcinomas. However, we have demonstrated that merely the very presence of the virus in a tumor provides the opportunity for a targeted therapeutic strategy. EBV persists in these tumors in a dormant or "latent" state. Many Herpes-family virus-infected cells can be killed by nucleoside analog antiviral pro-drugs like ganciclovir, which targe the viral thymidine kinase (TK) enzyme. EBV is resistant to these antiviral agents because latently-infected tumor cells do not express the viral (TK) enzyme. We have demonstrated that selected agents which induce the EBV-TK gene expression in the tumor cells renders the tumor susceptible to standard anti-viral agents. This is a tumor-targeted therapy, in that only the tumor cells (containing EBV) are killed - normal cells are spared. We have conducted a successful Phase I/II study of this virus-targeted therapeutic approach in patients with EBV-associated lymphoid malignancies, all of which were resistant to conventional radiation and chemotherapy. Our targeted therapy produced complete clinical responses (CRs) in 26% of patients, and good partial responses (PRs) in an additional 40% within one treatment cycle (total tumor response rate of 67%). This is an exceptionally high rate of response, and the adverse event profile was favorable. The overall goal of this SBIR proposal is to develop a more potent, more selective, and more patient-accessible virus-targeted therapeutic for testing in EBV+ malignancies. In our Phase I period, we have screened, validated, and selected a highly-potent, clinical-stage lead inducing agent, which is orally-available and has significant human safety data, for use in combination with an anti-viral agent for EBV lymphomas. In this Phase II proposal, we will complete the preclinical development of the virus-inducing agent for this specific indication, generate data to expand its potential therapeutic application and value, and prepare for a Phase II proof-of-concept clinical trial. Our Specific Aims in this Phase II Proposal are: 1.) Optimize lead compound - Refine this EBV/KSHV-targeted therapeutic regimen in animal models; 2.) Expand application of this therapeutic approach into other herpesvirus-associated malignancies; 3.) Complete pre-clinical development; 4.) Clinical trial planning and set-up. Measurable Outcomes and Deliverables: i.) Optimization of treatment regimen; ii.) Validation of this virus-targeted approach in other malignancies associated with γ-herpesviruses; iii.) Complete pre-clinical development of lead compound; iv.) Filing of IND for phase II clinical trial.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Topical Therapeutic to Promote Healing of Chronic Wounds
  • 批准号:
    8454815
  • 项目类别:
  • 资助金额:
    $21.93万
  • 财政年份:
    2013
  • 负责人:
    SUSAN Park PERRINE
  • 依托单位:
Next Generation Therapeutics for Hemoglobinopathies
  • 批准号:
    8250888
  • 项目类别:
  • 资助金额:
    $49.13万
  • 财政年份:
    2012
  • 负责人:
    SUSAN Park PERRINE
  • 依托单位:
Development of a clinical hemoglobin modulator
  • 批准号:
    8782071
  • 项目类别:
  • 资助金额:
    $50.0万
  • 财政年份:
    2011
  • 负责人:
    SUSAN Park PERRINE
  • 依托单位:
in vivo Studies of Clinical Stage Globin Modulators
  • 批准号:
    8202990
  • 项目类别:
  • 资助金额:
    $30.43万
  • 财政年份:
    2011
  • 负责人:
    SUSAN Park PERRINE
  • 依托单位:
海外基金